The present invention relates generally to mineral-dependent metabolic function in domesticated animals and more particularly to novel methods and materials for restoring and maintaining normal growth and development in livestock animals exposed to disruptive environmental conditions such as physical stress, micromineral dietary insufficiency and infectious disease.
While in continuous contact and exchange with the external environment, a living organism engages in continuing chemical change that comprises the organism's metabolism. The control of an organism's multitudinous metabolic processes (and the energy-yielding chemical reactions which make the processes possible) involves highly specific regulatory mechanisms, many of which are sensitive to the presence or absence of certain metallic elements in ionic or specifically chemically complexed forms.
In the higher orders of animals, and especially with respect to humans, the requirements, function and manifestation of deficiency of metallic elements such as sodium, iron, potassium, calcium, magnesium and non-metals such as chlorine and phosphorous are known with relative precision. Despite extensive research efforts, however, such nutritional characteristics for certain of the so-called "microminerals" (including manganese, copper, cobalt, zinc, chromium, selenium and molybdenum) are quite imprecisely know. Indeed, the available research data concerning micromineral nutritive function are often contradictory and/or inconclusive owing to the inordinate difficulty in establishing truly controlled experimental formats. What is known with any degree of certainty of the independent and associative functions of microminerals in the higher animals is frequently derived from in vitro experimentation on specific, isolated metabolic systems. Such information provides little or no guidance to those concerned with the problems of the long range maintenance of growth and development of large numbers of animals such as are encountered in livestock enterprises. The following brief notations of specific micromineral function and interrelations are believed to suitably illustrate the complexity of the state of the art knowledge with respect to micromineral nutrition.
Manganese is believed to have an activating function for many enzymes such as phosphoglucomutase, choline esterase, the oxidative .beta.-keto-decarboxylases, certain peptidases and muscle ATPase. In man, manganese salts are known to be poorly absorbed through the intestine and the ingestion of large quantities of manganese appears to interfere with the absorption of iron.
Copper's metabolic functions relate to its presence in tyrosinase, urate oxidase, dopamine-.beta.-hydroxylase, amine oxidases, cytochrome oxidase and cytoplasmic superoxide dismutase (in the latter, in combination with zinc). Copper deficiency in a manner of animals has been consistently correlated with malabsorption of dietary iron. Species-specific symptoms of copper deficiencies include anestrus and abortion in rats, spinal cord demyelinating disorders in sheep and arterial inelasticity in pigs. In the absence of sufficient dietary copper, many herbivores develop anemia and lesions of the skin and bones.
Cobalt is believed to be functional only as a component of vitamin B.sub.12 and the structurally related cobamide coenzymes which participate in a variety of metabolic functions. Nutritional requirements of these chemically complexed forms of cobalt are ordinarily satisfied by way of absorption of vitamin B.sub.12 produced by microorganisms comprising the intestinal flora of most higher animals. Omnivorous and carnivorous animals appear not to harbor microorganisms capable of B.sub.12 production and therefore metabolic requirements must ordinarily be met dietarily. Omnivores and carnivores are thus more readily subject to deficiency diseases.
Zinc is a constituent of numerous enzymes including carbonic anhydrase, the alcohol and lactate dehydrogenases and various peptidases. Zinc deficiencies are subject to widely varying manifestation depending on the species involved: retarded growth, alopecia, and topical lesions in rodents; parakeratosis in pigs; and poor growth and adolescent hypogonadism among humans. In humans, deficiencies are thought to arise most frequently in instances of ingestion of large quantities of a specific hexose phosphate, phytic acid, common in certain cereal grains and suspected of preventing absorption of zinc from the intestine. The same mechanism of deficiency may be involved with domesticated animals.
The status of molybdenum in animal nutrition is quite unclear. It is known to be a constituent of xanthine oxidase and several other enzymes. In herbivora, ingestion of even small amounts of molybdenum inexplicably results in increased copper requirements which, if not met, evoke copper deficiency symptoms.
Selenium function in higher animals is poorly understood. It is believed to combine with enzymes (i.e., glutathione peroxidases) necessary for reinstating cell membrane integrity disrupted by free radicals forming during electron transport in ATP formation. So-called "white muscle disease" in many species of animals as well as liver degeneration and pulmonary edema are frequently associated with selenium-deficient diets but large doses of selenium are known to be extremely toxic.
Chromium has been reported to be significant to proper carbohydrate metabolism in rodents but its specific function in this respect is not clear. It is commonly believed that chromium ions are required for insulin to associate with cell membrane receptor sites and that, in the absence of chromium, insulin-dependent entrance of glucose and acetate ions into cells is diminished.
As might be expected, oral administration of mineral supplements in frequently ineffective in treating deficiency symptoms because the nutritional "problem" often has its origins in malabsorption of particular minerals rather than dietary insufficiency. Parenteral administration of mineral supplements, on the other hand, is almost equally problematic. First, severe difficulties exist in co-solubilizing a plurality of mineral salts, making multiple injections necessary if more than one micromineral is to be administered. Second, many mineral sources are highly inflammatory and destructive of animal tissue when administered intramuscularly or even subcutaneously. Tissue damage is frequently the result of immunological response to the presence of metal ions which appear to operate as haptens. In livestock animals such inflammation and tissue destruction can substantially impair the value of the slaughtered animal.
Adding to the complexity of micromineral nutrition in livestock animals is the fact that maturative processes and environmental variations can precipitously vary the metabolic requirements of animals and hence their need for certain microminerals, frequently elevating the need for those substances which are not stored in any substantial quantity by the animals. Livestock animals express a wide variety of diseases which are known to be environmental stress-related but for which no prophylactic or curative methods and materials are readily available. As one example, sickness is an almost universal consequence of shipment and the transition from range environments and pasture feeding to confinement and so-called high energy concentrate feeding. Many of these disease conditions are felt to be micromineral balance-related. As further examples, animals which have been on micromineral deficient diets for prolonged periods, have endured prolonged systemic infections and/or have had severe diarrhea frequently develop hypogeusia, an apparent alteration in the sense of taste, resulting in progressive diminution of food intake leading to marasmus and death. Such conditions are not known to be treatable by oral administration of microminerals.
Finally, infectious diseases in livestock are also believed to bring about substantial variations in micromineral requirements owing to the involvement of immune system responses which have distinctly different micromineral requirements from those of normal metabolic systems. Correlatively, micromineral insufficiencies or imbalances are believed to impair normal immune function and therefore to contribute to susceptibility to viral and bacterial infection.
As a result of the above-noted complexities, advances in the science of micromineral nutrition have been marginal at best. For the most part, proposals of new methods and materials for restoring and maintaining suitable mineral balances in animals, including livestock animals, have either been overly broad and simplistic or overly narrow and directed to alleviation of symptoms of a specific, manifest micromineral deficiency disease state. The following examples of U.S. Patents relating to mineral nutrition are illustrative of the existing state of the art.
U.S. Pat. No. 2,798,023 relates broadly to oral preparations of "essential vitamins and minerals" especially suitable for ingestion by children and incorporating one or more salts of iodine, manganese, cobalt, potassium, molybdenum, iron, copper, zinc and magnesium. Typifying numerous generalized teachings of the art with respect to human nutrition, this reference ignores many significant aspects of mineral nutrition such as effectiveness of absorption of oral preparations through the intestine and variations in the need for minerals resulting from variations in environmental conditions.
U.S. Pat. No. 3,275,514 to Saltman et al. broadly comprehends the formation of chelates of calcium, magnesium, strontium, barium, titanium, vanadium, chromium, manganese, cobalt, nickel, copper and zinc with so-called "reducing sugars" and advocates, without reservation, the oral, intravenous and/or intramuscular administration of unspecified amounts of any one of all of these chelates.
U.S. Pat. No. 3,975,513 to Hecht et al. relates broadly to treatment of mineral deficiency diseases in young animals. The principal teaching of the patent is the construction and sizing of an iron compound-containing, orally administered bolus so that it will lodge in the stomach and be effective in piglets during the entire period prior to weaning. A collateral teaching of the reference is that unspecified quantities of "trace elements" and fluorine may suitably be administered in a similar manner by imbedding small particles of the elements or their compounds in the thermoplastic polymers from which the boluses are made.
U.S. Pat. No. 4,029,770 to Willard broadly asserts utility for oral and topical application of "catalyst or synergists" to animals with damaged or infected tissue as well as those encountering stress and/or shock. The catalysts consist of alkali metal silicates mixed with magnesium and calcium ion sources and a micelle-forming surfactant.
U.S. Pat. No. 3,829,566 to Burns et al. is specificaly directed to the control of degenerative muscle disease in mammals through administration of an assertedly synergistic combination of vitamin E (.alpha.-tocopherol) and selenium. The combination is said to be effective when administered parenterally, but orally effective only with non-herbivorous mammals owing to the interfering presence of sulfur, phosphorous and nitrates in customary diets of herbivores.
U.S. Pat. No. 3,923,982 to Lammand provides specific instructions assertedly useful in preventing "trace element deficiency" in animals through parenteral administration of oil suspensions of insoluble, non-ionizable copper, zinc or manganese metals or their oxides. The suspensions are assertedly only "moderately" inflammatory and less seriously tissue-damaging than other metal complexes involving admittedly more readily useful ions of the metals.
The above-noted representative U.S. Patents establish the existance of a long-standing need for nutritive materials and methods for restoring and maintaining normal micromineral dependent growth and development in animals, especially livestock animals, and most especially those exposed to physical stress, debilitating infectious diseases and dietary insufficiency. In their most desirable form, materials responsive to such needs would be characterized by comprehensiveness of micromineral nutrient content, simplicity of formulation, ease of administration, and the relative absence of inflammatory and/or immunogenic effects attending administration. The most desirable nutritive procedures would be characterized by simplicity and long-term efficacy of action in large scale practice involving groups of animals displaying wide variations in maturative state, nutritional history and degree of past or present exposure to infectious disease.